After transplantation, adult bone marrow-derived mesenchymal stem cells (BM-MSCs) may undergo transdifferentiation and/or cell fusion in response to new environments. However, the mechanism(s) that govern these cell fate switches remain unknown. Here we demonstrate that the pathology associated with murine Niemann-Pick disease type C (NP-C) cerebellum augments the ability of BM-MSCs to fuse with Purkinje neurons. The results suggest that the degenerative microenvironment of Purkinje neurons in the NP-C cerebellum modulates the cell fate switch of BM-MSCs via cell fusion.